Evolutionary rewiring of regulatory networks contributes to phenotypic differences between human and mouse orthologous genes
 Authors and Affiliations
 Authors and Affiliations
Doyeon Ha1, Donghyo Kim1, Inhae Kim2, Youngchul Oh1, JungHo Kong1, Seong Kyu Han1 and Sanguk Kim1,3,4,*
1Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea, 2ImmunoBiome Inc., Pohang, Korea, 3Graduate School of Artificial Intelligence, Pohang University of Science and Technology, Pohang, Korea and 4Institute of Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, Korea
*Corresponding author.
Abstract Mouse models have been engineered to reveal the biological mechanisms of human diseases based on an assumption. The assumption is that orthologous genes underlie conserved phenotypes across species. However, genetically modified mouse orthologs of human genes do not often recapitulate human disease phenotypes which might be due to the molecular evolution of phenotypic differences across species from the time of the last common ancestor. Here, we systematically investigated the evolutionary divergence of regulatory relationships between transcription factors (TFs) and target genes in functional modules, and found that the rewiring of gene regulatory networks (GRNs) contributes to the phenotypic discrepancies that occur between humans and mice. We confirmed that the rewired regulatory networks of orthologous genes contain a higher proportion of species-specific regulatory elements. Additionally, we verified that the divergence of target gene expression levels, which was triggered by network rewiring, could lead to phenotypic differences. Taken together, a careful consideration of evolutionary divergence in regulatory networks could be a novel strategy to understand the failure or success of mouse models to mimic human diseases. To help interpret mouse phenotypes in human disease studies, we provide quantitative comparisons of gene expression profiles on our website (http://sbi.postech.ac.kr/w/RN).
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